Surfactant is essential for normal lung function. By lowering surface tension at the alveolar air-liquid interface, it stabilizes alveoli which might otherwise collapse at lung volumes near functional residual capacity. In adult respiratory distress syndrome (ARDS), the interfacial properties of lung surfactant are markedly abnormal, resulting in alveolar collapse, decreased lung compliance, and intrapulmonary shunt with hypoxemia. The processes responsible for surfactant dysfunction in this setting have not been established. The goal of this project is to characterize the biochemical and biophysical changes in alveolar surfactant resulting from acute inflammation. Our interests are not only at the alveolar level, where changes in the surface tension forces in ARDS lead to parenchymal instability and collapse of these spaces, but also at the level of the molecules controlling the biophysics and mechanics of the interfacial layer. We propose to examine the hypothesis that surfactant dysfunction in ARDS is due to generation of novel chemical species which inhibit surfactant function by affecting its interfacial properties. Our preliminary results suggest that these compounds are the products of reactions involving native surfactant components, plasma proteins, and free radical species generated and released from inflammatory cells in the alveolar space during acute inflammation. Our analysis further demonstrates that "surfactant dysfunction" resulting from acute inflammation can be manifest in several different ways including an isolated increase in minimum surface tension during film compression, an isolated decrease in surface film elastance during dynamic cycling, or a combination of both. By using a recently developed analytical model of surface film behavior during dynamic oscillation, we have demonstrated that these distinct profiles of dysfunction can be explained by specific changes in surfactant dynamic biophysical properties (e.g. adsorption, desorption, squeeze out/film collapse kinetics). The experiments we propose will identify l) which chemical products generated by free radical reactions involving lung surfactant and serum proteins inhibit surfactant function, 2) what biophysical phenomena are involved with surfactant dysfunction, 3) how various changes in interfacial properties of surfactant identified in vitro affect lung function in vivo, and 4) the native lung's response to application of PEEP, changes in tidal volume, and exogenous surfactant administration as approaches to reversing dysfunction. By accomplishing these objectives, we will provide new information regarding which chemical components are most important for imparting adsorption, desorption, and film stability to native surfactant, how free radical-derived inhibitors affect each of these properties of surfactant and impact on overall interfacial properties, what the chemical source and composition of these inhibitor are, and how these inhibitors affect function in the intact lung. Potentially, these studies will suggest strategies for developing effective strategies for treatment of ARDS.